A Short synthesis of benzomorphane analgesics (±)-Metazocine and (±)-Phenazocine

Article abstract of DOI:10.1080/00397910903531722

A three step synthesis of (±)-metazocine and (±)-phenazocine starting with 3,4-lutidine is described. The key step involves Lewis acid promoted lithiation/electrophilic substitution reaction of N-alkyl-3,4-dimethyl- 1,2,5,6- tetrahydropyridine. Copyright

Full text of DOI:10.1080/00397910903531722

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A Short Synthesis of Benzomorphane
Analgesics (±)-Metazocine and (±)-
Phenazocine
Kamal Nain Singh a , Pushpinder Singh a , Arvind Kumar Sharma a ,
Paramjit Singh a & Satinder V. Kessar a
a Department of Chemistry , Panjab University , Chandigarh, India
Published online: 09 Nov 2010.
To cite this article: Kamal Nain Singh , Pushpinder Singh , Arvind Kumar Sharma , Paramjit Singh
& Satinder V. Kessar (2010) A Short Synthesis of Benzomorphane Analgesics (±)-Metazocine and
(±)-Phenazocine, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 40:24, 3716-3720, DOI: 10.1080/00397910903531722
To link to this article: http://dx.doi.org/10.1080/00397910903531722
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Synthetic Communications1, 40: 3716–3720, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903531722
A SHORT SYNTHESIS OF BENZOMORPHANE
ANALGESICS (ꢀ)-METAZOCINE AND
(ꢀ)-PHENAZOCINE
Kamal Nain Singh, Pushpinder Singh, Arvind Kumar Sharma,
Paramjit Singh, and Satinder V. Kessar
Department of Chemistry, Panjab University, Chandigarh, India
A three step synthesis of (ꢀ)-metazocine and (ꢀ)-phenazocine starting with 3,4-lutidine is
described. The key step involves Lewis acid promoted lithiation/electrophilic substitution
reaction of N-alkyl-3,4-dimethyl-1,2,5,6- tetrahydropyridine.
Keywords: Analgesics; a-azacarbanion; Lewis acid; lithiation; (ꢀ)-metazocine; (ꢀ)-phenazocine
INTRODUCTION
The natural opium alkaloids (ꢁ)-morphine (1a) and (ꢁ)-codeine (1b) and the
simple analogue morphinan (2) are important analgesic=antitussive agents.[1]
Although morphine is an important narcotic analgesic, it has undesirable addicitive
properties. Synthetic analogues containing benzomorphane ring system, i.e., 3 have
proven to be useful members in search for non addictive narcotic analgesics.[2] (ꢀ)-
Metazocine and (ꢀ)-phenazocine have been considered to be promising agents for
relief in pain in man at about one seventh the optimal dose of morphine. Further
their use appears to be attended with fewer and less objectionable side effects.[3]
Many syntheses for this class of compounds are reported in literature but most
of these involve multistep reactions and low yields.[4] Meyers et al. have achieved a
nine step asymmetric synthesis of (þ)-metazocine using a formamidine derived from
L-valinol as an internal auxiliary.[5] In the present paper we report a short three step
synthesis of (ꢀ)-metazocine and (ꢀ)-phenazocine with an overall yield of 42% and
Received August 18, 2009.
Address correspondence to Dr. Kamal Nain Singh, Department of Chemistry, Panjab University,
Sector 14, Chandigarh 160014, India. E-mail: kns@pu.ac.in
3716

A SHORT SYNTHESIS OF BENZOMORPHANE ANALGESICS
3717
27% respectively. The synthesis makes use of Lewis acid complexation methodology
for activation of tertiary amines.[6,7]
RESULTS
Reaction of 3,4-lutidine (6) with methyl iodide followed by reduction of pyridi-
nium salt with sodium borohydride gave N-methyl-3,4-dimethyl-1,2,5,6-tetra-
hydropyridine (7).[8] Treatment of 7 with one equivalent BF3 ꢂ OEt2 followed by
reaction with s-BuLi and p-methoxybenzyl chloride in THF at ꢁ78 ꢃC, afforded
the a-substituted product 11 in 76% yield. The reaction proceeds through the interme-
diacy of a-azacarbanion[6] and the lithiation seems to occur exclusively at carbon
atom adjacent to the Lewis acid complexed nitrogen atom, although three other
ꢄ
allylic centers (marked in 9=10) are present in the molecule and two of these are
primary. This high regioselectivity we believe is a consequence of lithium coordi-
nation with fluorine of N-complexed BF3 in the intermediate 9=10 or transition state
leading to them.[9] Simple reaction of 7 with s-BuLi=p-methoxybenzyl chloride, in the
absence of BF3 ꢂ OEt2, afforded untractable mixture of many products under a variety
of reaction conditions. The structure of 11 could be easily established on the basis of
1H NMR and 13C NMR spectrum. Grewe cyclisation[10] of 11, along with demethyla-
tion, proceeds cleanly with 48% hydrobromic acid to afford 4 in 62% yield.
Reaction of 3,4-lutidine with 2-phenylethyl bromide followed by reduction
with sodium borohydride gave N-(2-phenylethyl)-3,4-dimethyl-1,2,5,6-tetrahydro-
pyridine (8). Lithiation of BF3 complex of 8 followed by alkylation with
p-methoxybenzyl chloride gave 12 in 66% yield. Grewe cyclisation of 12 gave
(ꢀ)-phenazocine (5) in 64% yield with satisfactory spectroscopic data (Scheme 1).
Attempts to introduce enantioselectivity in lithiation=substitution step by using
(–)-sparteine as an external chiral ligand[11] are under progress.
Scheme 1.

3718
K. N. SINGH ET AL.
EXPERIMENTAL
N-Methyl-3,4-dimethyl-1,2,5,6-tetrahydropyridine (7)
To an ice cooled stirred solution of 3,4-lutidine (5 ml, 4.7 g, 44.5 mmol) in dry
diethyl ether (100 ml), methyl iodide (2.27 ml, 7.09 g, 50 mmol) was added and the
resulting solution was stirred for 24 hours at ambient temperature. The pyridinium
salt that precipitated out was filtered and washed thoroughly with diethyl ether. To
an ice cooled solution of this salt (10 g, 40.1 mmol) in 80% aqueous methanol
(100 ml) was added sodium borohydride (2.98 g, 80 mmol) in small portions. After
the completion of addition the solution was heated under reflux for 1 hour. Meth-
anol was removed under reduced pressure and water (50 ml) was added to the
residual mass. It was extracted with diethyl ether (5 ꢅ 40 ml) and the combined
organic layer was washed with brine and dried over anhydrous sodium sulphate
and concentrated in vacuo. The residue was distilled under reduced pressure to give
1
7 as a colorless liquid (4.6 g, 89%), bp 75–80 ꢃC=20 Torr. H NMR (CDCl3): d 1.6
(br s, 6H), 2.07 (m, 2H), 2.27 (s, 3H), 2.45 (m, 2H), 2.83 (dd, 2H). 13C NMR
(CDCl3): d 13.4, 15.6, 35.5, 41.0, 56.2, 62.6, 129.1, 130.5.
N-Methyl-2-(4’-methoxybenzyl)-3,4-dimethyl-1,2,5,6-
tetrahydropyridine (11)
Into a flame dried 50 ml two necked round bottom flask equipped with a stir
bar, septum cap and nitrogen bubbler, a solution of the amine 7 (0.59 g, 4.91 mmol)
in dry THF (15 ml) was taken. It was cooled to ꢁ78 ꢃC under nitrogen atmosphere
and BF3 ꢂ OEt2 (0.69 g, 0.6 ml, 4.91 mmol) was added. The contents were stirred for
10 min and s-BuLi (3.7 ml, 2.6 N, 9.82 mmol) was added and stirring was continued
for 30 min. The reaction mixture was quenched with p-methoxybenzyl chloride
(1.52 g, 1.32 mL, 9.82 mmol). After 10 min stirring at ꢁ78ꢃ, the temperature was
allowed to rise to ꢁ30ꢃ over a period of 30 min. The contents were then poured into
diethyl ether (50 ml) and extracted with 5% HCl (4 ꢅ 10 ml). The combined acidic
layer was made basic with solid Na2CO3 and extracted with chloroform (3 ꢅ 20 ml).
The combined organic layer was washed with water, brine and dried over anhydrous
sodium sulphate. The solvent was evaporated in vacuo and residual oil was subjected
to column chromatography over silica gel. Elution with hexane-ethyl acetate (6:4)
1
afforded compound 11 (0.91 g, 76%) as a pale yellow liquid. H NMR (CDCl3): d
1.5 (s, 3H), 1.65 (s, 3H), 1.72 (m, 1H), 2.05 (m, 2H), 2.35 (s, 3H), 2.53 (m, 1H),
2.75 (d, 2H), 2.9–3.0 (m, 2H), 3.79 (s, 3H), 6.79 (d, 2H), 7.15 (d, 2H). 13C NMR
(CDCl3): d 17.1, 18.5, 28.1, 36.3, 42.5, 46.1, 55.1, 67.1, 113.4, 125.2, 126.7, 129.9,
133.3, 157.5.
(ꢀ)-Metazocine (4)
A solution of the amine 11 (0.6 g) in 48% HBr (15 ml) was heated at 135ꢃ for
24 h. The cooled solution was diluted with water (20 ml) and made basic with
ammonium hydroxide. The mixture was extracted with chloroform (4 ꢅ 20 ml) and
the combined organic layer was washed with brine and dried over anhydrous sodium
sulphate. The solvent was removed in vacuo and residue was purified by column

A SHORT SYNTHESIS OF BENZOMORPHANE ANALGESICS
3719
chromatography over silica gel. Elution with hexane-ethylacetate-triethylamine
(60:35:5) afforded 4 (0.34 g, 62%) as an off white solid, mp 225–227 ꢃC, (lit.[3a] mp
1
228–233 ꢃC). H NMR (CDCl3): d 0.85 (d, 3H), 1.31 (s, 3H), 1.33–1.35 (m, 1H),
1.81 (dd, 1H), 1.89 (m, 1H), 2.14 (m, 1H), 2.41 (s, 3H), 2.46 (m, 1H), 2.62 (dd,
1H), 2.86 (m, 1H), 2.95 (d, 1H), 6.5 (dd, 1H), 6.69 (d, 1H), 6.91 (d, 1H). 13C
NMR (CDCl3): d 12.9, 22.7, 25.5, 36.3, 41.0, 41.6, 42.3, 47.2, 59.6, 112.6, 113.4,
127.2, 28.1, 142.6, 154.8. Anal. calced. for C15H21NO: C, 77.92; H, 9.09; N, 6.06.
Found: C, 77.98; H, 9.14; N, 5.94.
N-(2-Phenylethyl)-3,4-dimethyl-1,2,5,6-tetrahydropyridine (8)
Reaction of 3,4-lutidine (5 ml, 4.7 g, 44.5 mmol) with 2-phenylethyl bromide
(8.25 g, 44.5 mmol) and subsequent reduction with sodium borohydride, under the
conditions described for 7, gave the title compound 8 as a pale yellow liquid
1
(6.5 g, 70%), bp 110–115ꢃ=4 Torr. H NMR (CDCl3): d 1.65 (s, 3H), 1.71 (s, 3H),
2.25 (m, 4H), 2.6–2.7 (m, 4H), 2.83 (dd, 2H), 7.2 (m, 5H).
N-(2-Phenylethyl)-2-(4’-methoxybenzyl)-3,4-dimethyl-1,2,5,6-
tetrahydropyridine (12)
Reaction of amine 8 (0.5 g, 2.35 mmol) with BF3 ꢂ OEt2 (0.35 g, 0.33 ml,
4.91 mmol) and s-BuLi (1.8 ml, 2.6 N, 4.70 mmol) under the condition described for
7 followed by quenching with p-methoxybenzyl chloride (0.72 g, 0.62 ml, 4.7 mmol)
and usual workup and purification gave a-alkylated amine 12 (0.49 g, 64%) as a vis-
cous liquid. 1H NMR (CDCl3): d 1.48 (s, 3H), 1.7 (s, 3H), 2.1 (m, 2H), 2.55 (m, 3H),
2.69 (m, 2H), 2.73 (d, 2H), 2.95 (m, 2H), 3.7 (s, 3H), 6.76 (d, 2H), 7.1 (m, 5H), 7.35 (m,
2H). 13C NMR (CDCl3): d 12.2, 16.1, 35.6, 35.7, 37.9, 51.2, 54.7, 56.2, 62.5, 114.2,
125.7, 127.9, 128.1, 128.4, 128.9, 130.9, 132.5, 140.4, 159.2.
(ꢀ)-Phenazocine (5)
Reaction of amine 12 (0.3 g, 8.9 mmol) with 48% HBr (10 ml), under the
condition described for 11 and usual purification gave (ꢀ)-Phenazocine (5) (0.16 g,
59%), mp 179–181 ꢃC, lit.[12] mp (181–182 ꢃC).
1H NMR (CDCl3): d 0.91 (d, 3H), 1.34 (s, 3H), 1.41 (m, 1H), 1.82 (dd, 1H), 1.9
(m, 1H), 2.1 (d, 1H), 2.47 (m, 1H), 2.61 (dd, 1H), 2.65 (m, 2H), 2.69 (m, 2H), 2.89 (m,
1H), 2.97 (d, 1H), 6.4 (dd, 1H), 6.71 (d, 1H), 6.89 (d, 1H), 7.08 (m, 3H), 7.21 (m, 2H).
13C NMR (CDCl3): d 12.1, 25.2, 35.8, 36.1, 36.8, 37.2, 45.3, 46.5, 57.2, 60.4, 112.1,
112.4, 125.5, 127.9, 128.4, 128.7, 129.3, 140.2, 148.3, 154.2. Anal. calcd. for
C22H27NO: C, 82.20; H, 8.47; N, 4.36. Found: C, 82.15; H, 8.44; N, 4.32.
ACKNOWLEDGMENT
Financial support from CSIR (Scheme no. 01(2138)=07=EMR-II), New Delhi,
India is gratefully acknowledged.

3720
K. N. SINGH ET AL.
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